Efficient Solution-Phase Synthesis of 4,5,7-Trisubstituted Pyrrolo[3,2‑<i>d</i>]pyrimidines

We have developed an efficient and robust route to synthesize 4,5,7-trisubstituted pyrrolo­[3,2-<i>d</i>]­pyrimidines as potent kinase inhibitors. This solution-phase synthesis features a S_NAr substitution reaction, cross-coupling reaction, one-pot reduction/reductive amination and <i>N</i>-alkylation reaction. These reactions occur rapidly with high yields and have broad substrate scopes. A variety of groups can be selectively introduced into the N5 and C7 positions of 4,5,7-trisubstituted pyrrolopyrimidines at a late stage of the synthesis, thereby providing a highly efficient approach to explore the structure–activity relationships of pyrrolopyrimidine derivatives. Four synthetic analogs have been profiled against a panel of 48 kinases and a new and selective FLT3 inhibitor <b>9</b> is identified